Expression of the leptin receptor gene has been examined in mouse hypothalamns and other brain regions by in situ hybridization. With a probe recognizing all the known splice ~ariants, receptor mRNA was evident in several brain regions (cortex, hippocampus, thalamus), with strong expression in the hypothalamus (arcuate, ventromedial, paraventricniar and ventral premammillary nuclei), choroid plexus and leptomeninges. A probe specific to the long splice variant of the leptin receptor (Ob-Rb), containing the putative intracellniar signaling domain, again revealed strong expression in the hypothalamus; there was, however, minimal hybridization to choroid plexus and leptomeninges. These results indicate that the hypothalamus is a key site of leptin action, although other brain regions are also targeted.
Seasonal adaptations in physiology exhibited by many animals involve an interface between biological timing and specific neuroendocrine systems, but the molecular basis of this interface is unknown. In this study of Siberian hamsters, we show that the availability of thyroid hormone within the hypothalamus is a key determinant of seasonal transitions. The expression of the gene encoding type III deiodinase (Dio3) and Dio3 activity in vivo (catabolism of T(4) and T(3)) is dynamically and temporally regulated by photoperiod, consistent with the loss of hypothalamic T(3) concentrations under short photoperiods. Chronic replacement of T(3) in the hypothalamus of male hamsters exposed to short photoperiods, thus bypassing synthetic or catabolic deiodinase enzymes located in cells of the ependyma of the third ventricle, prevented the onset of short-day physiology: hamsters maintained a long-day body weight phenotype and failed to undergo testicular and epididymal regression. However, pelage moult to a winter coat was not affected. Type II deiodinase gene expression was not regulated by photoperiod in these hamsters. Collectively, these data point to a pivotal role for hypothalamic DIO3 and T(3) catabolism in seasonal cycles of body weight and reproduction in mammals.
Leptin is a 167-aa protein that is secreted from adipose tissue and is important in the regulation of energy balance. It also functions in hematopoiesis and reproduction. To assess whether leptin is involved in fetal growth and development we have examined the distribution of mRNAs encoding leptin and the leptin receptor (which has at least six splice variants) in the 14.5-day postcoitus mouse fetus and in the placenta using reverse transcription-PCR and in situ hybridization. High levels of gene expression for leptin, the leptin receptor, and the long splice variant of the leptin receptor with an intracellular signaling domain were observed in the placenta, fetal cartilage͞bone, and hair follicles. Receptor expression also was detected in the lung, as well as the leptomeninges and choroid plexus of the fetal brain. Western blotting and immunocytochemistry, using specific antibodies, demonstrated the presence of leptin and leptin receptor protein in these tissues. These results suggest that leptin may play a role in the growth and development of the fetus, both through placental and fetal expression of the leptin and leptin receptor genes. In the fetus, leptin may be multifunctional and have both paracrine and endocrine effects.
"Food addiction" has become a focus of interest for researchers attempting to explain certain processes and/or behaviors that may contribute to the development of obesity. Although the scientific discussion on "food addiction" is in its nascent stage, it has potentially important implications for treatment and prevention strategies. As such, it is important to critically reflect on the appropriateness of the term "food addiction", which combines the concepts of "substance-based" and behavioral addiction. The currently available evidence for a substance-based food addiction is poor, partly because systematic clinical and translational studies are still at an early stage. We do however view both animal and existing human data as consistent with the existence of addictive eating behavior. Accordingly, we stress that similar to other behaviors eating can become an addiction in thus predisposed individuals under specific environmental circumstances. Here, we introduce current diagnostic and neurobiological concepts of substance-related and non-substance-related addictive disorders, and highlight the similarities and dissimilarities between addiction and overeating. We conclude that "food addiction" is a misnomer because of the ambiguous connotation of a substance-related phenomenon. We instead propose the term "eating addiction" to underscore the behavioral addiction to eating; future research should attempt to define the diagnostic criteria for an eating addiction, for which DSM-5 now offers an umbrella via the introduction on Non-Substance-Related Disorders within the category Substance-Related and Addictive Disorders.
Leptin, the protein product of the adipose tissue-specific ob (obese) gene (1), reduces the body weight, adiposity and food intake of obese ob/ob mice on peripheral or central injection (2, 3, 4). [125I]leptin binding has been detected in mouse choroid plexus (5), from which a leptin receptor gene was expression cloned (5). The gene has at least 6 splice variants (6, 7). Leptin receptor mRNA was localized in the hypothalamus by in situ hybridization being particularly abundantly expressed in the arcuate nucleus (8). There is evidence linking the physiological effects of injected leptin with hypothalamic neuropeptide Y (9, 10) (NPY), which has potent central effects on food intake and energy balance (11), and is also expressed in the arcuate nucleus. Here we report dual in situ hybridization studies for leptin receptor and NPY gene expression in the mouse arcuate nucleus, where the majority of cells examined expressed both genes. This provides the first direct evidence that leptin acts on cells that express NPY mRNA.
Siberian hamsters decreased body weight by 30% during 18 wk in short day (SD) vs. long day (LD) controls. Subsequent imposed food deprivation (FD; 24 h) caused a further 10% decrease. In the hypothalamic arcuate nucleus (ARC), SDs reduced proopiomelanocortin (POMC) gene expression and agouti-related protein (AGRP) mRNA was elevated, changes that summate to reduced catabolic drive through the melanocortin receptors. There was no effect of photoperiod on neuropeptide Y (NPY), melanin concentrating hormone, orexin, or corticotropin-releasing factor mRNAs. Superimposed FD increased AGRP gene expression and caused a localized elevation of NPY mRNA in the ARC. Both adipose tissue leptin and ARC leptin receptor (OB-Rb) mRNAs were downregulated in SDs, whereas FD increased OB-Rb gene expression. Thus OB-Rb mRNA is differentially regulated by acute and chronic changes in plasma leptin in this species. In a separate experiment in LDs, AGRP gene expression was increased by 24 or 48 h FD, whereas POMC mRNA was downregulated in the caudal ARC. AGRP and NPY mRNAs were extensively coexpressed in the ARC, and their differential regulation by photoperiod and FD is suggestive of transcript-specific regulation at the level of individual neurons.
The discovery of leptin, the product of the ob gene, has led to major developments in understanding the regulation of energy balance. It is now recognised that leptin is produced in several organs additional to white adipose tissue, including brown fat, the placenta and fetal tissues (such as heart and bone/cartilage). The hormone has multiple functions-in inhibiting food intake, in the stimulation/maintenance of energy expenditure, as a signal to the reproductive system and as a 'metabolic' hormone influencing a range of processes (for example, insulin secretion, lipolysis, sugar transport). The production of leptin by white fat is subject to a number of regulatory influences, including insulin and glucocorticoids (which are stimulatory), and fasting and beta-adrenoceptor agonists (which are inhibitory). A key role in the regulation of leptin production by white fat is envisaged for the sympathetic system, operating through beta3-adrenoceptors. The leptin receptor gene is widely expressed, with the several splice variants exhibiting different patterns of expression. The long form variant (Ob-Rb) is expressed particularly in the hypothalamus, although it is being increasingly identified in other tissues. Leptin exerts its central effects through several neuroendocrine systems, including neuropeptide Y, glucagon-like peptide-1, melanocortins, corticotrophin releasing hormone (CRH) and cocaine- and amphetamine-regulated transcript (CART). In essence, the leptin system now appears highly complex, the hormone being involved in a range of physiological processes in a manner far transcending the initial lipostatic concept. This complexity may reduce the potential of the leptin system as a target for anti-obesity therapy.
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